The relative concentrations of parent drug and a large number of the metabolites of the phenothiazine drugs, chlorpromazine, thioridazine and mesoridazine, can be determined in various types of biological specimens by a new GC/MS/COM method. The automated GC/MS/ COM procedures permit simultaneous assays of parent drug, up to l2 of its metabolites and 3 internal standards in a single run, thereby allowing the construction of a drug metabolism "profile" of each patient, facilitating correlation of biochemical and clinical parameters. It was found during the first year of studies under this grant, that most GC procedures yield excessive values for unchanged parent phenothiazine drug (sulfide form) while its sulfoxide and N-oxide metabolites are underestimated due to their thermal decomposition. A procedure for minimizing this pyrolysis has been developed, methods for extraction of the drug fractions from the biological material have been optimized and suitable internal standard for the clinically important chemical classes of metabolites (e.g., sulfide, sulfoxide, sulfone, etc.) have been prepared. Blood, urine, saliva and various tissues will be examined in an attempt to correlate metabolic pathways with therapeutic responses, age, and toxic side effects.